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Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming [ChIP-seq]

ABSTRACT: Specific inhibition of HDAC7 expression with subtype specific siRNAs results in inhibition of the interaction of H3.3 with HIRA, while the association of H3.3 with DAXX and H3K9me3 is significantly increased, resulting in H3.3 being deposited on H3K9me3+/DAPI+ heterochromatin nuclear foci with observed changes in RNA expression. Inhibition of HDAC7 triggers a significant increase of heterochromatin marks H3K9me3 and H3K27me3, global heterochromatin spreading in cancer cells, and reprogramming of the H3.3 chromatin landscape. We performed H3K9me3 chip-seq in glioma stem cells following HDAC7 knockdown in order to identify specific sites of heterochromatin spreading and/or increased occupancy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286176 | GEO | 2026/01/07

REPOSITORIES: GEO

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Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming [RNA-seq]

Project description:Class IIa histone deacetylases (HDACs) are a family of enzymes that despite their name, do not have any measurable histone deacetylase activity but they function as multi-protein interaction hubs due to the presence of a prolonged N-terminal domain. Here we show that HDAC7, a member of the Class IIa HDAC family, is a chaperone for Histone H3.3 and, interacts with H3.3 and HIRA on chromatin. Specific inhibition of HDAC7 expression with subtype specific siRNAs results in inhibition of the interaction of H3.3 with HIRA, while the association of H3.3 with DAXX and H3K9me3 is significantly increased, resulting in H3.3 being deposited on H3K9me3+/DAPI+ heterochromatin nuclear foci with observed changes in RNA expression. This drives substantial alteration of cancer cell gene expression as well as inhibition of the stemness phenotype for cancer cells. To understand the genome wide effect on expression, we perform RNA-seq following HDAC7 knockdown.

2026-01-07 | GSE286177 | GEO

Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming

Project description:Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming

| PRJNA1208064 | ENA

Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming [RNA-seq]

Project description:Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming [RNA-seq]

| PRJNA1208069 | ENA

Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming [ChIP-seq]

Project description:Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming [ChIP-seq]

| PRJNA1208062 | ENA

DAXX adds a de novo H3.3K9me3 deposition pathway to the histone chaperone network (part 2)

Project description:A multitude of histone chaperones are required to support histones from their biosynthesis until DNA deposition. They cooperate through the formation of histone co-chaperone complexes, but the crosstalk between nucleosome assembly pathways remains enigmatic. Using exploratory interactomics, we define the interplay between histone H3–H4 chaperones in the histone chaperone network. We identify several novel histone dependent complexes and predict the structure of the ASF1 and SPT2 co-chaperone complex, expanding the role of ASF1 in histone dynamics. We show that DAXX provides a unique functionality to the histone chaperone network, recruiting histone methyltransferases to promote H3K9me3 catalysis on new histone H3.3–H4 prior to deposition onto DNA. Hereby, DAXX provides a molecular mechanism for de novo H3K9me3 deposition and heterochromatin assembly. Collectively, our findings provide a framework for understanding how cells orchestrate histone supply and employ targeted deposition of modified histones to underpin specialized chromatin states.

2023-03-02 | PXD038263 | Pride

DAXX adds a de novo H3.3K9me3 deposition pathway to the histone chaperone network (part 1)

2023-03-02 | PXD034888 | Pride

Phosphorylation of HP1/Swi6 tunes chromatin a¬ffinity and relieves inhibition on Suv39/Clr4 H3K9 trimethyl spreading.

Project description:Heterochromatin formation in Schizosaccharomyces pombe requires the spreading of histone 3 (H3) Lysine 9 (K9) methylation (me) from nucleation centers by the H3K9 methylase, Suv39/Clr4, and the reader protein, HP1/Swi6. To accomplish this, Suv39/Clr4 and HP1/Swi6 have to associate with nucleosomes both nonspecifically, binding DNA and octamer surfaces and specifically, via recognition of methylated H3K9 by their respective chromodomains. However, how both proteins avoid competition for the same nucleosomes in this process is unclear. Here, we show that phosphorylation tunes the nucleosome affinity of HP1/Swi6 such that it preferentially partitions onto Suv39/Clr4’s trimethyl product rather than its unmethylated substrates. Preferential partitioning enables efficient conversion from di-to trimethylation on nucleosomes in vitro and H3K9me3 spreading in vivo. Together, our data suggests that phosphorylation of HP1/Swi6 creates a regime that relieves competition with the “read-write” mechanism of Suv39/Clr4 for productive heterochromatin spreading.

2025-12-22 | PXD057316 | Pride

Leo1 is a Global Regulator of Heterochromatin Cis-spreading

Project description:Domains of heterochromatin play important roles in the maintenance and regulation of eukaryotic genomes. However, the repressive nature of heterochromatin combined with its propensity to self-propagate necessitates the existence of robust mechanisms that limit heterochromatin spreading and thereby avoid silencing of expressed genes. A number of specific sequence elements have been found to serve as barriers to heterochromatin spreading; however, the mechanisms by which spreading is curtailed are generally not well understood. Here we uncover a role for PAF complex component Leo1 in regulating heterochromatin cis-spreading. A genetic screen revealed that loss of Leo1 results in spreading of heterochromatin across a centromeric (IRC) boundary element in fission yeast. Similar heterochromatin spreading was seen upon deletion of other components of the PAF complex, but not other factors involved in transcription-coupled chromatin modification, indicating a specific role for the PAF complex in heterochromatin regulation. Loss of Leo1 is associated with reduced levels of H4K16 acetylation at the boundary, while tethering of the H4K16 acetyltransferase Mst1 to boundary chromatin suppresses heterochromatin spreading in leo1? cells, suggesting that Leo1 antagonises heterochromatin spreading by facilitating H4K16 acetylation. Interestingly, Leo1 also regulates heterochromatin spreading independently of boundaries, and loss of Leo1 causes redistribution of heterochromatin, in particular resulting in substantial expansion of telomeric heterochromatin domains. The PAF complex is known to be an important regulator of transcription-related chromatin modifications; our findings reveal a previously undescribed role for this complex in global regulation of heterochromatin spreading in cis. 8 samples: input (whole cell extract) and IP from H3K9me2 ChIP in wild-type and leo1? cells, in duplicate

2015-05-22 | E-GEOD-61688 | biostudies-arrayexpress

Tumor suppressor functions of DAXX through histone H3.3 deposition pathway in pancreatic neuroendocrine tumor

Project description:Purpose: Pancreatic neuroendocrine tumors (PanNETs) have considerable malignant potential. Frequent somatic mutations and loss of DAXX protein expression have been frequently found in PanNETs. DAXX is known as a transcriptional repressor, however, molecular functions underlying loss of DAXX remain unclear in PanNETs. Experimental Design: We evaluated DAXX-knockdown (KD) and -knockout (KO) PanNET cells were analyzed for in vitro and vivo. The target genes were screened by microarray and chromatin immunoprecipitation (ChIP) assays for DAXX, histone H3.3 and H3K9me3 complex. Results: Microarray and ChIP analyses of DAXX-KD/KO identified 13 genes as the direct targets of DAXX transcriptional repressor. Among them, 5 genes were suppressed by DAXX/H3.3/H3K9me3 pathway. DAXX-KD/KO increased sphere forming activity, but it was suppressed by knockdown of the target gene. In xenograft models, tumorigenicity was significantly increased in DAXX-KO cells with high expression of the target. Clinically, higher recurrence was recognized in PanNETs with low expression of DAXX and high expression of the target than others. Conclusions: DAXX plays as a tumor suppressor and DAXX/H3.3 complex suppresses target genes by promoting H3K9me3 in PanNETs. DAXX and its target molecule might be effective biomarkers and therapeutic candidates.

2018-06-28 | GSE93050 | GEO

Leo1 is a Global Regulator of Heterochromatin Cis-spreading

Project description:Domains of heterochromatin play important roles in the maintenance and regulation of eukaryotic genomes. However, the repressive nature of heterochromatin combined with its propensity to self-propagate necessitates the existence of robust mechanisms that limit heterochromatin spreading and thereby avoid silencing of expressed genes. A number of specific sequence elements have been found to serve as barriers to heterochromatin spreading; however, the mechanisms by which spreading is curtailed are generally not well understood. Here we uncover a role for PAF complex component Leo1 in regulating heterochromatin cis-spreading. A genetic screen revealed that loss of Leo1 results in spreading of heterochromatin across a centromeric (IRC) boundary element in fission yeast. Similar heterochromatin spreading was seen upon deletion of other components of the PAF complex, but not other factors involved in transcription-coupled chromatin modification, indicating a specific role for the PAF complex in heterochromatin regulation. Loss of Leo1 is associated with reduced levels of H4K16 acetylation at the boundary, while tethering of the H4K16 acetyltransferase Mst1 to boundary chromatin suppresses heterochromatin spreading in leo1Δ cells, suggesting that Leo1 antagonises heterochromatin spreading by facilitating H4K16 acetylation. Interestingly, Leo1 also regulates heterochromatin spreading independently of boundaries, and loss of Leo1 causes redistribution of heterochromatin, in particular resulting in substantial expansion of telomeric heterochromatin domains. The PAF complex is known to be an important regulator of transcription-related chromatin modifications; our findings reveal a previously undescribed role for this complex in global regulation of heterochromatin spreading in cis.

2015-05-22 | GSE61688 | GEO

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